Prospective study to evaluate radioactive iodine of 20 mCi vs 10–15 mCi in Graves’ disease

Objectives To assess whether increasing radioactive iodine dose can increase treatment efficacy in Graves’ disease. Methods A prospective study was conducted, including 106 patients receiving 20 mCi (740 MBq) radioactive iodine (RAI), compared with a retrospective data, including 113 patients receiving 10–15 mCi (370–555 MBq) RAI. Remission and failure rates were evaluated at 6 months post-RAI. Statistical analysis was performed using logistic regression and Kaplan–Meier curves. Results Patients receiving 20 mCi RAI demonstrated a significantly higher remission rate compared to the 10–15 mCi group (82.1% vs 66.4%, p = 0.009). Median time to remission was shorter in the 20 mCI group (3 vs 4 months, p = 0.002). Hypothyroidism at 6 months was more prevalent in the 20 mCi group (67% vs 53%, p = 0.03). Larger thyroid size (> 60 g) was associated with treatment failure (p = 0.02). Conclusions Higher dosage (20 mCi) RAI showed superior efficacy in achieving remission compared to lower dosages (10–15 mCi) in Graves’ disease treatment.


Background
Graves' disease (GD) is the most common cause of hyperthyroidism [1].It is an autoimmune disease and presents a significant challenge in clinical management due to its diverse manifestations and potential complications [2].Radioactive iodine (RAI) therapy stands as a cornerstone in the treatment options, offering a targeted approach to cure thyroid overactivity.The goal is to provide sufficient radiation dose to make the patient hypothyroid.This result can be done by a fixed dose method or a calculating dose method with the same effectiveness [3].Both cannot guarantee remission, but the calculating one requires additional time and computation.Therefore, many institutions have stopped using the calculating method and prefer the fixed dose method.The optimal dosage of RAI for achieving remission is recommended with 10-15 mCi (370-555 MBq) [4] which shows a remission rate of 90% [5][6][7][8].However, there are some reports regarding a lower remission rate of about 50-80% [9][10][11][12].Correlation between the remission after RAI therapy and administered radiation dose is seen in some studies [6,[13][14][15][16].This prospective study aims to address the benefit of increasing radiation dose by comparing the efficacy of two RAI dosages: 20 mCi (740 MBq) vs 10-15 mCi (370-555 MBq).

Subjects
We used retrospective data, including 113 patients with GD who received RAI 10-15 mCi in the previous year between April 2021 -June 2022 at the Phrapokklao

Data collection
Clinical and laboratory data were collected before the treatment for 1-2 months and after the treatment every 1-2 months until 6 months.

Protocol for RAI therapy
All patients were advised to stop antithyroid drugs (ATD) and take low iodine diet for 7 days before RAI.RAI was administered with a fixed dose basis of 10-15 mCi for the retrospective group and 20 mCi for the prospective group.Thyroid gland size and thyroid uptake were not used to determine the RAI dose.Thyroid uptake was not measured in this study due to increased hospital visits and clinical non-significance.ATD and regular diet were resumed 3 days after RAI.

Definition of remission and failure
The outcomes were measured at 6 months after RAI.Remission was defined as euthyroid without ATD for a month, hypothyroid or thyroxin requirement.Failure was defined as persistent hyperthyroid or unable to withdraw ATD.The study was approved by the Chanthaburi Research Ethics Committee (COA032/65).All experimental protocols were approved by Chanthaburi Research Ethics Committee.Informed consents were obtained from all subjects and/or their legal guardian(s).

Statistical analysis
The baseline characteristics of the two groups were compared using chi-square or Fisher's exact test for qualitative data and t-test or Mann Whitney U test for quantitative data.We used logistic regression analysis to evaluate factors associated with treatment failure and Kaplan-Meier curves with log-rank test to compare cumulative remission rates of the two groups.A twosided p-value of less than 0.05 was considered statistically significant.The data were analyzed using IBM SPSS Statistics (Version 29).
Thyroid size was a significant predictor for a treatment failure (p = 0.002) (Table 2).There was no correlation among other clinical features.The thyroid size cutoff more than 60 g was associated with RAI treatment failure (p = 0.02).
Subgroup analysis of patients with thyroid gland size 60 g or less compared to more than 60 g (Table 3).Patients with thyroid gland size with 60 g or less had better response to RAI.Although, with larger gland size, RAI 20 mCi had better remission rate but not statistically significant.
We did not see any progression or new development of ophthalmopathy.However, we observed some adverse events between both groups (Table 4).All events were mild and resolved without hospitalization.No differences in any events for one patient in 10-15 mCi vs 20 mCi group (32.7% vs 40.6%, p = 0.2).Nevertheless, there were trends of adverse events toward the 20 mCi in nausea and vomiting, neck tenderness, and sorethroat.

Discussion
Our findings indicate that the higher RAI dosage of 20 mCi led to a significantly higher remission rate compared to the lower dosage range of 10-15 mCi.This result aligns with previous studies suggesting a correlation between administered radiation dose and treatment outcomes [15].Some studies showed no difference in increasing radiation doses which could be caused by low statistical power [5,11].In some circumstances, lower remission of 50-80% [9,12,15] might not be acceptable for patients and physicians.This lower remission rate could be explained by iodine repletion status in Thailand [18] and other countries [15,19].The iodine consumption of Thai adults is 11.5 g for adults, which is far higher than the recommendation by World Health Organization (WHO) of 150 mcg/d [20].Importantly, the median time to remission was shorter in the 20 mCi group in our study, suggesting a more rapid onset of therapeutic effect with the higher dosage.This finding has potential implications for patient management, as a shorter time to remission may translate to faster resolution of symptoms and a quicker return to euthyroid status.Additionally, the higher proportion of patients presenting with hypothyroidism at 6 months in the 20 mCi group highlights the effectiveness of this dosage in achieving the desired therapeutic outcome.However, the smaller gland size of the 20 mCi group could affect the remission rate (p = 0.023).
Thyroid size appeared as a significant predictor of treatment failure, with larger thyroid glands (> 60 g) associated with a higher risk of failure.This outcome aligns with the previous literatures [8-10, 21, 22].We did not find other significant factors previously mentioned such as male sex and free T4 [8,23].Thyroid with a smaller gland size seems to response well to RAI and even better with higher radiation dose, unfortunately with gland size more than 60 g, the effectiveness did not improve in this study.This finding emphasizes the importance of considering individual patient characteristics in treatment decision-making and dosage selection.Future studies could explore additional factors contributing to treatment response and failure to further optimize patient outcomes.
In terms of safety, we observed mild adverse events in both dosage groups, with no significant differences between the 10-15 mCi and 20 mCi groups.These findings suggest that the higher dosage of 20 mCi was well-tolerated and did not result in a disproportionate increase in adverse events.However, in some adverse events, we observed more in the RAI 20 mCi group which could be explained by worsened hyperthyroid after receiving the RAI [24,25].All events were mild and resolved without hospitalization.Nevertheless, continued monitoring of adverse events and long-term outcomes is warranted to ensure the safety of RAI therapy in patients with GD.
There are some concerns about cancer risk regarding RAI treatment.The data from the Cooperative Thyrotoxicosis Therapy Follow-up Study (CTTFUS) showed no difference of the solid cancer standard mortality ratio among patients treated with radioactive iodine, surgery, or antithyroid drugs, although, there was a dose response relationship between RAI dose and solid cancer mortality [26,27].Minimal risk of malignancy was also observed in other studies [28,29].The counseling for RAI seems reasonable to neglect small cancer risk, as compared to antithyroid drugs or surgery [30].We think that increasing radiation dose for more treatment efficacy might improve patients' overall health and reduce the risk of receiving additional radiation, in case of treatment failure.
Limitations of our study include its non-randomized and non-double blinded nature and potential confounding factors that were not accounted for in the analysis.Additionally, the relatively short follow-up period of 6 months may not capture long-term treatment outcomes and recurrence rates, however, these 6 months period is practical in our practice [4].Future research could address these limitations by conducting randomized controlled trials with longer follow-up periods and comprehensive outcome assessments.
In conclusion, this prospective study highlights the efficacy of RAI 20 mCi in GD treatment, offering faster remission and higher success rates compared to lower

Table 1
Baseline characteristics of patients with Graves' disease, according to radioactive iodine dose administration 10-15 mCi vs 20 mCi [17]st patients used methimazole (MMI) before RAI.There were 3 patients in the 20 mCi group who used propylthiouracil (PTU) instead of MMI before the RAI.The PTU doses were converted to MMI by divided by 10[17].One patient did not receive ATD before the RAI.Ophthalmopathy was seen in 15 patients in the 10-15 mCi group and 13 patients in the 20 mCi group.These patients had mild degree and inactive disease.In the 10-15 mCi group, 18 patients received RAI 10 mCi and 95 patients received RAI 15 mCi.There were 3 patients who had thyroid nodule They underwent thyroid scans and revealed diffuse thyroid uptake with a cold nodule.Fine needle aspirations were done and proved to be benign.Two patients got tested with TSH receptor antibody and reported high level.The values are mean ± SD or median (quartile 1st-3rd) RAI Radioactive iodine, BMI Body mass index, MMI Methimazole

Table 2
Factors associated with radioactive iodine treatment failure using logistic regression analysis

Table 3
Subgroup analysis of patients with thyroid gland size ≤ 60 g vs > 60 g

Table 4
Adverse events, number of patients (%) dosages.Individualized treatment based on thyroid size is crucial for optimizing outcomes in GD patients.